Annals of Oncology Advance Access originally published online on June 4, 2008
Annals of Oncology 2008 19(10):1742-1748; doi:10.1093/annonc/mdn375
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gastrointestinal tumors |
Phase I study of biweekly oxaliplatin, gemcitabine and capecitabine in patients with advanced upper gastrointestinal malignancies
1 Division of Medical Oncology, Washington University School of Medicine, St Louis
2 Center for Hematology/Oncology, Boynton Beach
3 Division of Molecular Oncology
4 Division of Biostatistics, Washington University School of Medicine, St Louis
5 Division of Hematology/Oncology, University of Virginia, Charlottesville
6 UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, USA
* Correspondence to: Dr B. R. Tan, Washington University School of Medicine, 660 South Euclid Avenue, Box 8056, St Louis, MO 63110, USA. Tel: +314-362-5737; Fax: +314-362-7086; E-mail: btan{at}im.wustl.edu
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Abstract |
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Background: Oxaliplatin, gemcitabine and capecitabine are all active agents against upper gastrointestinal and pancreaticobiliary cancers.
Patients and methods: Patients with upper gastrointestinal malignancies treated with 0–2 prior chemotherapy regimens received oxaliplatin (85–100 mg/m2) as a 2-h i.v. infusion with gemcitabine (800–1000 mg/m2) at a constant rate i.v. infusion (CI) of 10 mg/m2/min on days 1 and 15 of a 28-day cycle. Capecitabine (600–800 mg/m2) was administered orally twice a day on days 1–7 and 15–21. A three per cohort dose escalation schema was used to determine the maximum tolerated dose (MTD) and the dose-limiting toxic effects (DLTs) of this combination regimen.
Results: Thirty patients with advanced upper gastrointestinal malignancies were enrolled. The MTD was defined as oxaliplatin 100 mg/m2 i.v. over 2 h plus gemcitabine 800 mg/m2 i.v. at a CI of 10 mg/m2/min on days 1 and 15 with capecitabine 800 mg/m2 p.o. b.i.d. days 1–7 and 15–21 of a 29-day cycle. DLTs include grade 3 fatigue and grade 3 dyspnea. One complete and two partial responses were observed.
Conclusions: This biweekly schedule of oxaliplatin, gemcitabine and capecitabine is tolerable and warrants further investigation in biliary and pancreatic malignancies.
Key words: Capecitabine, gemcitabine, oxaliplatin, upper gastrointestinal malignancies
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Effective treatment for patients with advanced upper gastrointestinal malignancies, including pancreaticobiliary cancer, is limited. Outcomes are uniformly poor for these patients with median survivals of 6–12 months using current standard regimens [1–5]. Oxaliplatin, a diaminocyclohexane platinum compound, has activity against upper gastrointestinal cancers such as pancreatic, gastroesophageal and biliary cancers [6–8]. In combination with gemcitabine, response rates of 26.8% in pancreatic cancer patients [7, 9] and 36%–50% in biliary tract cancers were observed [10, 11]. Regimens utilizing oxaliplatin combined with the oral fluoropyrimidine, capecitabine, were associated with a 48% response rate and a median survival of 11.2 months in patients with advanced gastroesophageal tumors [12]. Moreover, a recent meta-analysis indicates that compared with single-agent gemcitabine, a combination of gemcitabine plus capecitabine or gemcitabine plus a platinum improved efficacy in pancreatic cancer [13]. Gemcitabine plus capecitabine is also an active regimen against biliary tract cancers with responses of
30% [14, 15]. On the basis of these considerations, we carried out a phase I study incorporating escalating doses of oxaliplatin with gemcitabine and capecitabine for patients with advanced upper gastrointestinal malignancies. To improve tolerability and possibly efficacy, both oxaliplatin and gemcitabine were given on a biweekly schedule while capecitabine was given on a 1-week on/1-week off schedule. Capecitabine administered on a similar schedule combined with oxaliplatin resulted in higher response rates and progression-free survival compared with a 2-week on/1-week off capecitabine schedule in patients with advanced colorectal cancer [16]. Gemcitabine was also administered intravenously at a constant infusion rate of 10 mg/m2/min on the basis of early phase I data establishing that at this infusion rate, the accumulation of the active metabolite, gemcitabine triphosphate, in mononuclear cells is optimized [17–19]. This study was designed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of this combination regimen. Safety and toxic effects associated with this regimen were also evaluated.
If markers for outcome or toxicity are identified by incorporating retrospective pharmacogenetics analysis into a phase I study, subsequent trials could take into account DNA polymorphism status. Consequently, in this study, potentially functional DNA variants in the oxaliplatin (ERCC2 K751Q, GSTP1 I105V) and capecitabine (TYMS TSER, TYMS TSERG>C and TYMSdel) pathways [20] were assessed. Other published functional variants, e.g. CDA A70T [21] from the gemcitabine pathway occur at too low a frequency for statistical analysis in the current sample size and were excluded from the study.
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patients and methods |
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patient eligibility
Eligibility criteria included patients 18 years or older with pathologically confirmed advanced gastrointestinal malignancy; presence of measurable or evaluable disease (by physical examination, radiology or tumor marker); a life expectancy of
8 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two. Patients must have recovered from the acute toxic effects of all prior chemotherapy, radiotherapy or other targeted anticancer therapy. Patients must have received 
2 prior chemotherapy regimens (0–2) with no chemotherapy or radiotherapy given within 3 weeks before the start of protocol treatment. Other requirements included adequate bone marrow function [peripheral absolute neutrophil count (ANC) 1500 cells/mm3, platelet count 100 000 cells/mm3 and hemoglobin 9 g/dl]; adequate hepatic and renal functions (total serum bilirubin less than or equal to the institutional upper limit of normal, serum transaminases less than or equal to four times the institutional upper limit of normal and serum creatinine of 2.0 mg/dl or creatinine clearance of 60 ml/min/1.73 m2 for patients with creatinine levels >2.0 mg/dl). Other exclusion criteria include presence of active central nervous system metastases; grade 2 or higher peripheral neuropathy; known hypersensitivity to oxaliplatin, gemcitabine or capecitabine and uncontrolled intercurrent illness. Pregnant and lactating patients were excluded from the study. All patients gave written consent before study entry in compliance with institutional and federal guidelines.
treatment
Protocol treatment consisted of up to six 28-day cycles of chemotherapy. Oxaliplatin (EloxatinTM; Sanofi-Aventis Inc., New York, NY) was provided by Sanofi-Aventis Inc. Gemcitabine hydrochloride (Gemzar®; Eli Lilly and Company, Indianapolis, IN) and capecitabine (Xeloda®; Roche Pharmaceuticals, Nutley, NJ) were obtained commercially. Gemcitabine was administered intravenously at a constant infusion rate of 10 mg/m2/min followed by intravenous oxaliplatin over 120 min on days 1 and 15. Capecitabine was administered orally twice a day on days 1–7 and days 15–21. Oral doses were rounded off to the nearest 150- or 500-mg tablet. The dose levels investigated are summarized in Table 1.
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Within 14 days before study treatment, patients were required to undergo a complete history, physical examination, PS, neurologic and medication assessment, laboratory studies including complete blood count (CBC), chemistries, pregnancy test, and imaging assessment. Toxicity assessments, PS, CBC and chemistry were done every 2 weeks. A neurologic assessment was recorded every 4 weeks. Tumor measurements were repeated every 8 weeks.
definition of DLT
Adverse events were reported using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events, version 3.0 (NCI CTCAE V 3.0; available from http://ctep.info.nih.gov/CTC3/ctc.html). All adverse events were reported, regardless of attribution. DLT was defined as grade 4 neutropenia lasting 7 days in duration, grade 3 neutropenia associated with fever or infection, grade 4 anemia or thrombocytopenia, grade 3 or 4 non-hematologic toxic effects with the exception of grade 3 nausea and vomiting or grade 3 hepatic toxicity which resolves to grade 1 or less before the next treatment course. Any toxicity requiring a 2-week delay between cycles was also considered dose limiting.
dose escalation and dose modification
Three to six patients were enrolled at each dose level. No intrapatient dose escalation was allowed. Dose escalation proceeded to the next dose level only if no DLTs were observed among the first three patients at any given dose level during the first cycle. At the occurrence of a DLT, up to three more patients were enrolled at the same dose level. If only one out of the six patients developed a DLT, escalation proceeded to the next dose level. If two or more patients developed DLTs, escalation was halted. The MTD was defined as one dose level below that in which DLTs were observed in two or more patients from a cohort of two to six patients. An additional six patients were accrued at the defined MTD to fully evaluate any toxicity encountered.
Treatment was delayed on a weekly basis for ANC 1500 cells/mm3, platelet count 100 000 cells/mm3. Chemotherapy resumed only when these values were reached and only when all grade 3 or 4 toxic effects had resolved to grade 1 or 2. Except for grade 3 or 4 peripheral neuropathy, upon resumption of chemotherapy, doses were reduced to the prior dose levels. For patients who experienced grade 3 or greater peripheral neuropathy, only the oxaliplatin dose was reduced by 25% after the toxicity resolved to grade 2 or less.
disease assessment
Each patient's disease status was assessed using the Response Evaluation Criteria in Solid Tumors. Complete response (CR) was defined as the disappearance of all measurable disease or normalization of tumor markers for a minimum of 4 weeks. Partial response (PR) was defined as a 30% reduction in the sum of the unidimensional measurement of measurable disease or a 50% reduction in tumor marker levels, for a minimum of 4 weeks. Stable disease (SD) was defined as a <30% decrease and a <20% increase in the sum of the unidimensional measurement of measurable disease with no new lesions. Progressive disease (PD) was defined as 20% increase in the measurements or the occurrence of any new lesion.
pharmacogenetic studies
We also evaluated the relationship between tumor response and genetic variants involved in drug metabolism of oxaliplatin and capecitabine. Patient genomic DNA was isolated using Gentra Puregene kit (Gentra Systems, Inc., Minneapolis, MN) following the manufacturers’ instructions. Genotyping was carried out using PCR (TYMS TSER), RFLP (TYMS TSERG>C) or Pyrosequencing (ERCC2 K751Q, GSTP1 I105V and TYMSdel) as previously described [22–26]. The Fisher's exact test was used to determine the association between tumor response and genetic variants. A P value <0.05 was taken to indicate significance and all statistical tests were two-sided.
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patient characteristics
Thirty patients were enrolled between March 2005 and August 2006. Table 2 summarizes the distribution of various baseline patient characteristics. The median age of study participants was 62 years (range 38–78 years). The majority of patients presented with advanced pancreatic cancer (63.3%) and biliary cancer (20%). Seventy percent of patients had an ECOG PS of one. Two-thirds (20 of 30) of patients received prior chemotherapy and 26.7% received prior abdominal radiotherapy. Four patients received gemcitabine-based adjuvant therapy, 10 patients received one prior chemotherapy regimen and six patients received two prior therapies.
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DLT and MTD
The number of patients assigned to each dose level is listed in Table 3. No DLTs were noted in cohorts 1–2. Two additional patients were enrolled in cohort 1 because two patients did not receive all study drugs during cycle 1. In cohort 3, two patients experienced early disease progression before the completion of one cycle. Dose escalation proceeded after the three assessable patients developed no DLTs during cycle 1. Among the first three patients treated at dose level 4, one patient developed a DLT (grade 3 fatigue). As a result, three more patients were enrolled, among which one patient developed a DLT (grade 3 dyspnea associated with transient grade 4 thrombocytopenia). Since two out of six patients in this cohort developed DLT, subsequent dose escalation was halted. An additional three patients were enrolled at the previous level, dose level 3. One out of the six assessable patients in cohort 3 developed DLT (grade 3 fatigue). Therefore, dose level 3 was determined to be the MTD of this regimen. An additional eight patients were enrolled at the MTD (one patient had prolonged treatment delays attributable to pre-existing myelodysplastic syndrome and another withdrew consent and entered into hospice). No DLTs occurred among the additional patients enrolled at level 3, although one patient developed a grade 4 thrombocytopenia which resolved within 1 week. Thus, the MTD for this regimen was declared to be oxaliplatin at 100 mg/m2 i.v. days 1 and 15, gemcitabine at 800 mg/m2 administered at a constant infusion rate of 10 mg/m2/min on days 1 and 15 plus capecitabine at 800 mg/m2 orally twice a day on days 1–7 and 15–21.
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hematologic and non-hematologic toxic effects
Among the 30 patients enrolled, a total of 90.5 cycles of chemotherapy cycles were administered with a mean of three cycles (range 0.5–7 cycles). One-third of patients (10 of 30) received at least 6 months of study treatment with no disease progression. All 10 patients discontinued therapy secondary to oxaliplatin-associated cumulative peripheral neuropathy. Another patient with SD discontinued therapy after five cycles due to grade 2 hypersensitivity reaction to oxaliplatin.
Table 4 summarizes the mean nadir ANC, hemoglobin and platelet counts during cycle 1 and all other cycles by cohort. During cycle 1, only three patients developed transient grade 3–4 neutropenia (one in cohort 3 and two in cohort 4) while two patients developed grade 4 thrombocytopenia (one each in cohorts 3 and 4). During all other cycles, only one patient developed grade 3 neutropenia and one patient experienced grade 3 thrombocytopenia.
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Table 5 lists the non-hematologic toxic effects encountered during all treatment cycles among all cohorts. The most common toxic effects encountered include fatigue, anorexia, constipation, diarrhea, nausea, vomiting, transaminitis and peripheral neuropathy. However, very few grade 3–4 toxic effects occurred except for oxaliplatin-related cumulative toxic effects.
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response, disease progression and survival
Considering all 30 patients, 23 completed at least two cycles of therapy and had follow-up radiological response assessment. Three patients did not complete two cycles due to DLT, while three others had early clinical progression and one withdrew consent.
A patient with metastatic pancreatic cancer who progressed after prior gemcitabine (±bevacizumab) treated at dose level 4 achieved a CR (lasting for 3 months) and survived 26 months after his initial study treatment. Two patients treated at dose level 3, the MTD, had PRs. A patient with metastatic cholangiocarcinoma who progressed through two prior regimens (5-FU and gemcitabine) achieved a 67% reduction in tumor burden and survived for 19 months while a 42-year-old woman with metastatic mucinous adenocarcinoma with no prior therapy experienced a 47% reduction in her measurable disease and a 99% decrease in her Ca 19-9 from 7964 to 90 U/ml. She continues to be followed and is now 24 months since her study enrollment. Nine other patients (two each from cohorts 1, 2 and 4 and three from cohort 3) had SD lasting for at least 4 months. Those with SD include six patients with pancreatic cancer, two patients with cholangiocarcinoma and one patient with duodenal adenocarcinoma.
Among the 19 patients with pancreatic cancer, 15 were assessable for response. Seventy-four percent (14 of 19) had prior gemcitabine-based therapy, three of which were in the adjuvant setting. One patient whose tumor progressed after first-line gemcitabine treatment achieved a CR, six other patients had SD and eight patients progressed. The median survival for all patients with pancreatic cancer was 5.1 months (95% confidence interval of 2.8–10.2 months). Median survival for pancreatic cancer patients whose best response is SD or better (CR + PR + SD) was significantly better at 13.4 versus 3.3 months for patients with progressive disease or those who experienced DLT (P = 0.0051). Five of the six patients with biliary cancer were assessable for response. One patient achieved a PR while two others had SD. These three patients with clinical benefit (PR + SD) all had prior chemotherapy. Median survival for patients with biliary tract cancers was 8.35 months (range 2–19.4 months).
Among the 10 patients with no prior therapy, one patient had a PR, four had SD and five had PD. Two of the four patients who received adjuvant gemcitabine therapy had SD. Among the 10 patients who had one prior therapy, one had a CR, four had SD, four had PD and one was not assessable. For the six patients with two prior therapies, one had a PR, two had SD and three were inassessable.
pharmacogenetic correlates
The number of patients with various candidate genotypes and the corresponding percentage of patients with nonprogression as best response (CR + PR + SD) are summarized in Table 6. Our results showed no association between the progression/nonprogression rates with the functional DNA variants in the oxaliplatin (ERCC2 K751Q) and capecitabine (TYMS TSER, TYMS TSERG>C and TYMSdel) pathways tested. However, there was a trend towards better response among patients heterozygous for the GSTP1 I105V genotype (P = 0.132). Due to the small sample size included in this phase I study, no firm conclusions could be drawn regarding association of these genotypic variants with outcomes.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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This phase I study evaluated the safety profile and MTD of a biweekly schedule of oxaliplatin, gemcitabine and capecitabine in patients with upper gastrointestinal tumors. The DLTs of this regimen include grade 3 fatigue and grade 3 dyspnea. This regimen and schedule appears to be very tolerable with very few grade 3–4 toxic effects. The MTD of this regimen was oxaliplatin at 100 mg/m2 i.v. days 1 and 15, gemcitabine at 800 mg/m2 administered at a constant infusion rate of 10 mg/m2/min on days 1 and 15 plus capecitabine at 800 mg/m2 orally twice a day on days 1–7 and 15–21. There was also activity of this regimen in upper aerodigestive and pancreaticobiliary tumors.
For patients with upper gastrointestinal malignancies, fluoropyrimidine- and platinum-based therapies continue to be the mainstay agents for gastroesophageal tumors, while gemcitabine-based regimens remain a standard for pancreaticobiliary cancers. To our knowledge, this is the first study to utilize this triplet combination using the 1-week on/1-week off schedule of capecitabine combined with both oxaliplatin and constant infusion rate gemcitabine administered in a biweekly schedule. Preclinical studies demonstrated gemcitabine enhanced cytotoxicity of oxaliplatin and fluoropyrimidines [27]. Several phase I–II studies have evaluated the triplet combination of gemcitabine with a platinum and 5-FU using different schedules and dosages. Goel et al. [28] utilized continuous infusion 5-FU administered over 2 weeks with gemcitabine administered on days 1 and 8 and oxaliplatin on day 1 of a 21-day cycle. The recommended phase II dose of this 5-FU/oxaliplatin/gemcitabine combination was 200/100/450 mg/m2. A multicenter Arbeitsgemeinschaft Internistische Onkologie study evaluated weekly high dose 5-FU infusion at 1500 mg/m2 over 24 h, weekly gemcitabine at 900 mg/m2 and oxaliplatin at 65 mg/m2 days 1 and 8 of a 21-day cycle [29]. The tumor response rate among 43 pancreatic cancer patients was 19% with median survival of 7.5 months. For patients with gall-bladder carcinoma, this same regimen conferred a median survival of 9.9 months and was tolerated well [30]. For inoperable esophageal cancer, the MTD was declared to be oxaliplatin 60 mg/m2, gemcitabine at 1000 mg/m2 with 5-FU 750 mg/m2 over 24 h on days 1 and 8 of a 21-day cycle [31]. All the above studies demonstrated activity and tolerability of the three-drug combination in gastrointestinal malignancies.
A biweekly administration of oxaliplatin, gemcitabine and infusional 5-FU allows for the administration of therapeutic doses of all 3 drugs [32, 33]. The GOLF regimen achieved a 42% response rate and a median survival of 22 months among metastatic colorectal cancer patients using 85 mg/m2 of oxaliplatin, 1000 mg/m2 of gemcitabine and 400 mg bolus plus 800 mg/m2 22-h infusion of 5-FU [32]. With this schedule, very few grade 3–4 toxic effects were observed. A response rate of 56% was achieved among patients with advanced gastric cancer treated with gemcitabine plus FOLFOX [33]. Again, toxic effects were minimal with this schedule.
Our study demonstrated that this triplet regimen of oxaliplatin, gemcitabine and capecitabine administered on a biweekly schedule is tolerable at full or near-full drug dosages for patients with upper gastrointestinal malignancies. Most of the patients treated in this study had prior chemotherapy and 25% received prior gastrointestinal radiation. Toxic effects were mainly grade 1–2. Although antitumor responses were not a primary objective of this trial, it was encouraging to observe a CR and two PRs as well as several SDs with this combination. A median survival of 13 months for patients with pancreatic cancer who achieved a response or SD with this regimen is also encouraging. These results warrant further phase II investigation of this combination and schedule for the first-line therapy of patients with pancreatic and biliary cancers.
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Sanofi-Aventis Pharmaceuticals.
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This study was presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, 1–5 June 2007, Chicago, IL. We are grateful to Dr Ira Steinberg for his helpful comments.
Received for publication April 1, 2008. Revision received May 1, 2008. Accepted for publication May 2, 2008.
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